The discovery that gut microbiota can influence behavior is emerging as an exciting new concept in neurophysiology and disease. In humans, links have been drawn between the gut microbiome and neurological disorders such as depression, migraine, anxiety, autism, schizophrenia, and neurodegenerative disorders. However, the question of causality in microbiome studies remains unanswered and the molecular basis of the complex interaction of diet, microbiota, and the brain is still poorly understood. The goal of this proposal is to identify microbiome factors that contribute to neural function and to uncover an important mechanistic link between diet, gut microbiota, and neurological disorders. The nematode C. elegans is ideally suited for this approach because both its neural circuits and bacterial diets are simple, well-defined and genetically tractable. We have generated and characterized a C. elegans model for a channelopathy that provides a sensitized genetic background to study gut-brain interactions. Specifically, we have isolated a novel gain-of-function (gf) mutation in the neuronal voltage-gated calcium channel gene unc-2/CaV2?. Similar mutations in human ortholog, CACNA1A, cause Familial Hemiplegic Migraine-type I (FHM1) in humans. C. elegans unc-2/CaV2?(FHM1) mutants have increased synaptic transmission and display clonic seizures. We made the striking observation that a diet of bacteria that make vitamin B12 greatly reduces the seizure behavior of unc-2/CaV2?(FHM1) mutants. Vitamin B12 is an essential nutrient for brain health. Vitamin B12 deficiency has been associated with many neurological disorders, including depression, schizophrenia, Alzheimer's and migraine. However, how vitamin B12 impacts neural function is largely unclear. We will determine how vitamin B12 changes metabolic processes in the gut, and how such changes impair neural function in the brain. In addition, we will take advantage of our unique C. elegans migraine model to identify beneficial microbiota and other factors that improve neural health. These experiments will provide valuable understanding into elusive mechanisms of gut-brain communication and can ultimately inform the use of probiotics to improve symptoms of neurological disorders.